Assessing Needs and Perceptions of Research Participation in Pediatric-Onset Multiple Sclerosis: A Multistakeholder Survey.

BACKGROUND: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey. METHODS: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS). RESULTS: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs. CONCLUSIONS: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation.

Gene-environment interactions and risk of pediatric-onset multiple sclerosis associated with time spent outdoors.

BACKGROUND: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.

A not so incidental 'incidentaloma' - pediatric ganglioneuroma-associated cerebellar degeneration and super-refractory status epilepticus: case report and literature review.

Paraneoplastic neurological disorders are rare in children, with paraneoplastic cerebellar degeneration (PCD) considered highly atypical. We describe a 13-year-old girl with progressive neurobehavioral regression, cerebellar ataxia, and intractable epilepsy presenting in super-refractory status epilepticus. After an extensive evaluation, her clinical picture was suggestive of probable autoimmune encephalitis (AE). Further diagnostic testing revealed a molecularly undefined neural-restricted autoantibody in both serum and CSF, raising suspicion over an adrenal mass previously considered incidental. Surgical resection led to a robust clinical improvement, and pathology revealed a benign ganglioneuroma. This report widens the spectrum of paraneoplastic manifestations of ganglioneuroma, reviews the diagnostic approach to antibody-negative pediatric AE, and raises important clinical considerations regarding benign and incidentally found tumors in the setting of a suspected paraneoplastic neurologic syndrome.

Demographic Features and Clinical Course of Patients With Pediatric-Onset Multiple Sclerosis on Newer Disease-Modifying Treatments.

BACKGROUND: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). METHODS: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. RESULTS: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. CONCLUSIONS: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population.

Pediatric anti-NMDA-receptor autoimmune encephalitis in siblings: Developmental, Electrophysiologic, and Genetic Implications.

BACKGROUND: Anti-NMDAR encephalitis is a leading cause of autoimmune encephalitis in children. Untreated disease can lead to long-term neurological disability. CASE REPORT: We present siblings with pediatric-onset anti-NMDAR encephalitis. One was treated early, while the other's diagnosis and treatment were delayed by several years. Developmental, electrophysiologic, and genetic implications are discussed. CONCLUSION: Anti-NMDAR encephalitis is a severely debilitating disease that often requires prompt initiation and early escalation in treatment. Delayed treatment may lead to irreversible neurological sequalae. Further studies exploring associations between timing and tier of treatment initiation and longitudinal outcomes are needed.

Silent findings: Examination of asymptomatic demyelination in a pediatric US cohort.

BACKGROUND AND OBJECTIVES: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. METHODS: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. RESULTS: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. CONCLUSION: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.

High titers of myelin oligodendrocyte glycoprotein antibody are only observed close to clinical events in pediatrics.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis. OBJECTIVE: To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers. METHODS: Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity. RESULTS: We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics. CONCLUSION: Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.

Papilledema in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): A Pediatric Case and Review of the Literature.

OBJECTIVE: To analyze the available literature on papilledema in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), report the first detailed pediatric case, and explore the underlying pathophysiology. METHODS: First, we conducted a comprehensive literature review of all cases of papilledema in CIDP. Next, we reviewed each case, incorporating only those including cerebrospinal fluid analysis into the results. Finally, we present our pediatric patient. RESULTS: Our literature review yielded a total of 9 adult and no pediatric cases. Cerebrospinal fluid protein and opening pressures were elevated in all cases. They were also elevated in our pediatric case. CONCLUSION: Prolonged periods of active immune-mediated inflammation is likely a cause of papilledema in adult CIDP, and possibly also in our pediatric case.

Possible Biases of Researchers' Attitudes Toward Video Games: Publication Trends Analysis of the Medical Literature (1980-2013).

BACKGROUND: The study of video games is expanding, and so is the debate regarding their possible positive and deleterious effects. As controversies continue, several researchers have expressed their concerns about substantial biases existing in the field, which might lead to the creation of a skewed picture, both in the professional and in the lay literature. However, no study has tried to examine this issue quantitatively. OBJECTIVE: The objective of our study was to examine possible systematic biases in the literature, by analyzing the publication trends of the medical and life sciences literature regarding video games. METHODS: We performed a complete and systematic PubMed search up to December 31, 2013. We assessed all 1927 articles deemed relevant for their attitude toward video games according to the focus, hypothesis, and authors' interpretation of the study results, using a 3-category outcome (positive, negative, and neutral). We assessed the prevalence of different attitudes for possible association with year of publication, location of researchers, academic discipline, methodological research, and centrality of the publishing journals. RESULTS: The attitude toward video games presented in publications varied by year of publication, location, academic discipline, and methodological research applied (P<.001 for all). Moreover, representation of different attitudes differed according to centrality of the journals, as measured by their impact factor (P<.001). CONCLUSIONS: The results suggest that context, whether scientific or social, is related to researchers' attitudes toward video games. Readers, both lay and professional, should weigh these contextual variables when interpreting studies' results, in light of the possible bias they carry. The results also support a need for a more balanced, open-minded approach toward video games, as it is likely that this complex phenomenon carries novel opportunities as well as new hazards.

Screening questionnaires for parkinsonism: a systematic review.

Parkinson's disease (PD) is a common, treatable movement disorder that often remains undiagnosed despite clinically manifest symptoms. Screening for parkinsonism could lead to improved detection and earlier treatment, and facilitate research studies of PD prevalence. In order to determine the feasibility of screening, this study evaluated the validity of previously developed screening questionnaires. We systematically searched online databases PubMed and EMBASE for English-language studies published between 1980 and 2009. In each database a "Parkinson(s) disease" or "parkinsonism" term was combined with a screening term ("screening instrument," "screening questionnaire," "screen" or "prevalence survey") and a validity term ("validation," "sensitivity" and "specificity"). Included studies reported the psychometric properties of at least one self-report questionnaire for parkinsonism. Twenty-seven studies met the inclusion criteria. From these studies, 9 screening questionnaires were identified. Sensitivity and specificity estimates varied widely. Sensitivity estimates were as high as 100% when questionnaires were tested among previously diagnosed PD patients and included a high number of parkinsonism specific items, but were as low as 48% when tested among early cases in a community-based sample. Specificity estimates were lower, ranging from 22 to 100%. An older sample, presence of multiple co-morbid conditions and lower literacy led to lower specificity estimates. Higher specificity estimates were seen when the screening questionnaires were administered by a physician. Screening questionnaires can detect symptomatic parkinsonism. However, the performance of these questionnaires varied based on the individual items, study sample, and method of administration. The performance of screening questionnaires in the detection of early or mild parkinsonism was modest.